Atomoxetine: An Non-Stimulant for AD/HD

Atomoxetine, brand name, Strattera, was approved by the FDA for distribution in November 2002. It became available in US pharmacies in early 2003. Despite its hefty price tag, it is becoming widely used for adults and children with Attention Deficit Hyperactivity Disorder. (AD/HD) It is a non-stimulant medication approved for the treatment of AD/HD in both children and adults. The stimulants include methylphenidate (Ritalin, Concerta and Metadate CD) and amphetamine (Dexedrine, Dexedrine Spansules, and Adderall XR). Stimulants are FDA approved for the treatment of AD/HD in children and adolescents, but most physicians consider them the first line medication treatment for AD/HD in adults too.

How Does It Work?

Atomoxetine is a selective norepinephrine reuptake inhibitor. This means that it strengthens the chemical signal between those nerves that use norepinephrine to send messages. Atomoxetine does not appear to affect the dopamine systems as directly as do the stimulants. Atomoxetine does not seem to cause an increase in brain dopamine levels in the nucleus accumbens or the striatum areas of the brain. The stimulants appear to cause an increase in the availability of dopamine in these areas. The effect on the nucleus accumbens is believed to cause euphoria and to be responsible for the stimulants’ abuse liability. Dopamine increases in the striatum may be associated with the risk of motor tics.(1)

Although Atomoxetine’s direct effect only seems to be with norepinephrine, it appears to cause a secondary increase in dopamine levels in the prefrontal cortex area of the brain. (the brain area behind the eyes.) This part of the brain is associated with the ability to mentally rehearse responses, and inhibit impulsivity. The area is also associated with working memory.

Atomoxetine’s chemical structure bears some similarities to the tricyclic antidepressants although it is actually a phenylpropanolamine derivative. The tricyclic antidepressants include desipramine and imipramine. These two medications have been shown to be effective treatments for AD/HD in adults and children but do not have FDA approval for this use. The tricyclics affect norepinephrine but are not as specific as atomoxetine. It is the tricyclics’ effect on neurotransmitters other than dopamine and norepinephrine that appear to cause their drawbacks. Their anticholinergic effects can cause constipation, dry mouth and dry eyes. Their antihistaminergic effects can cause weight gain and tiredness. Their alpha adrenergic effects can cause tremor and changes in blood pressure. The tricyclics can cause a delay in cardiac conduction. This effect can cause minor – and in rare cases – serious changes in heart rhythm. Investigators have evaluated atomoxetine carefully for cardiac rhythm and blood pressure changes. Minor, but insignificant, increases in pulse and blood pressure were noted. Atomoxetine did not appear to cause changes in cardiac conduction. (2)

Can you abuse Atomoxetine?

Some physicians have been reluctant to prescribe stimulants for adults because they are Schedule II and are officially listed as having a significant potential for addiction. Although stimulants can indeed be abused, their use does not seem to cause abuse individuals who do not already have a substance abuse problem.(3) However there are other ways in which stimulants can be abused. Because they decrease sleepiness and cut appetite, individuals might use them to cram for exams or lose weight. Atomoxetine appears to have minimal abuse potential. Thus, it is not as highly controlled as the stimulants. It can inhibit sleep or appetite but does so much less than the stimulants. Thus, it is less likely to be passed around.

Does Atomoxetine have side effects?

The side effects of atomoxetine may include many of the side effects seen with stimulants. These common effects include appetite suppression, sleep disturbance jitteriness and irritability. Since there is a small increase in pulse and blood pressure, these should be monitored in patients with cardiac disease. However, these effects are often milder than those of the stimulants. Atomoxetine can cause a significant problem with nausea. In my experience, this is the most common reason for individuals stopping the drug. Taking it with meals or splitting the dose may help. Atomoxetine is most commonly given as a single dose in the morning. However there are some individuals who cannot tolerate this because they actually find the medication to be sedating. Atomoxetine can lead to urinary retention in some individuals. It can also cause problems with sexual functioning. Some individuals experience sexual side effects. such as impotence, erectile difficulties and difficulty achieving orgasm.(4) Stimulants often cause the individual to feel more alert and less sleepy. Atomoxetine can occasionally do this to a milder degree. In many individuals, individuals, however, Atomoxetine can actually cause sleepiness. I have several patients who prefer to take it at night. Atomoxetine does not usually have a rebound effect. Although the compound is metabolized quickly, the clinical effects appear to last all day and even into the following morning. This can be a good thing for individuals who find that stimulants make them feel irritable in the evenings. However, people who need to stimulant “kick” to help them focus may be disappointed in the new drug.

In December 2004, Lilly Pharmaceuticals announced that it was adding a warning about atomoxetine (Strattera) and hepatitis. Two cases of severe hepatitis were reported associated with the use of this medication. Both cases resolved after the medication was stopped. Patients should contact their physician if they notice signs of possible hepatitis: Dark urine, yellowing of skin or eyes, or upper abdominal pain. It should be noted that only 2 cases have been reported and over 2 million people have taken atomoxetine.

How Strong and How Fast?

Stimulants start to work in less than an hour. Because of this, one can rapidly determine the best dose. Atomoxetine has a more subtle, gradual onset. One must increase the dose over several days or weeks. One may not see the maximum effect of a given dose for about three weeks. In some cases, I may do a cross over in which the individual takes a lower dose of the stimulant while waiting for the atomoxetine to take its full effect. Limited studies have suggested that atomoxetine is equally effective to methylphenidate (Ritalin) for a variety of AD/HD symptoms.(2) In my own experience, this is not always true. Some individuals experience even the highest recommended doses of the drug as less effective than the conventional stimulants.

Atomoxetine is metabolized through the cytochrome P-450 2D6 pathway. However the major metabolite is also active. The activity of the CYP 2D6 system can vary widely in perfectly healthy people. Individuals who metabolize it slowly will build up a higher level faster than those who metabolize it rapidly. Because of this, we may not be able to achieve an effective dose in some individuals within the FDA dosage guidelines. Fluoxetine (Prozac) and paroxetine (Paxil), as well as other drugs affect the metabolism of atomoxetine. If one is taking atomoxetine it is important to check with the doctor or pharmacist to make sure that the atomoxetine does not interfere with other medications that the individual is taking.

A Double Edged Sword?

Some of the advantages of atomoxetine may be a double edged sword. Its lower abuse potential might make us more willing to prescribe it for individuals with a substance abuse problem. Its weak antidepressant effect might make us more comfortable prescribing it for individuals who might have co-morbid depression. However this should not relieve clinicians from the responsibility for assessing and treating co-morbid substance abuse and mood problems. Atomoxetine is more convenient because you can call in refills. However, one of the major reasons for failure for AD/HD medication treatment failure is inadequate follow up with infrequent dosage monitoring and adjustments. Medication management visits can be therapeutic. Frequent visits also help pick up changes in the patient’s clinical condition.

So, Where Does Atomoxetine Fit In?

I still recommend the stimulants as the first-line drugs for AD/HD. They have stood the test of time. We are familiar with their strengths and their side effects. Their quick onset enables the clinician to more rapidly adjust the dose. The stimulants – even the newer ones – are less expensive than atomoxetine. I have found a number of patients who feel that even the higher doses of atomoxetine are not as effective as the stimulants. However there are many people who do not respond to stimulants or who cannot tolerate the side effects. I have achieved excellent results in a number of individuals who felt jumpy or irritable on stimulants. For these people, atomoxetine can be an excellent medication.

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